The biological and pathological function of the presenilin-1 Delta exon 9 mutation is independent of its defect to undergo proteolytic processing

The two homologous presenilins are key factors for the generation of amyloi d beta-peptide (A beta), since Alzheimer's disease (AD)-associated mutation s enhance the production of the pathologically relevant 42-amino acid A bet a (A beta 42), and a gene knockout of presenilin-1 (PS1) significantly inhi bits total A beta production. Presenilins undergo proteolytic processing wi thin the domain encoded by exon 9, a process that may be closely related to their biological and pathological activity. An AD-associated mutation with in the PS1 gene deletes exon 9 (PS1 Delta exon9) due to a splicing error an d results in the accumulation of the uncleaved full-length protein. We now demonstrate the unexpected finding that the pathological activity of PS1 De lta exon9 is independent of its lack to undergo proteolytic processing, but is rather due to a point mutation (S290C) occurring at the aberrant exon 8 /10 splice junction. Mutagenizing the cysteine residue at position 290 to t he original serine residue completely inhibits the pathological activity in regard to the elevated production of A beta 42. Like PS1 Delta exon9, the resulting presenilin variant (PS1 Delta exon9 C290S) accumulates as an uncl eaved protein and fully replaces endogenous presenilin fragments. Moreover, PS1 Delta exon9 C290S exhibits a significantly increased biological activi ty in a highly sensitive in vivo assay as compared with the AD-associated m utation. Therefore not only the increased A beta 42 production but also the decreased biological function of PS1 Delta exon9 is due to a point mutatio n and independent of the lack of proteolytic processing.